The only solution to the HIV epidemic in the developing world is a vaccine that either prevents infection or reduces transmission. We will define efficacious cellular immune responses against the AIDS virus and will attempt to engender these responses by vaccination. The correlates of protective immunity against HIV remain a mystery. To help resolve this mystery, we seek to identify which of the many different CD8+ lymphocyte responses present during the acute phase of AIDS virus infection actually contribute to reducing viral replication. We will identify at least five CD8+ lymphocyte epitopes for incorporation into a multi-epitope vaccine regimen. These epitopes should be recognized in the acute phase, induce CD8+ lymphocytes that efficiently control viral replication, and are derived from regions of the viral genome in which variation exacts a cost to viral fitness. We have developed two specific aims to address the hypothesis that effective CD8+ lymphocytes directed against at least five epitopes that are derived from regions under functional and structural constraints will control replication of SIV. In Specific Aim I we will define efficacious CD8+ lymphocyte responses against epitopes derived from regions of the virus that are under functional constraints. In Specific Aim II we will carry out vaccine efficacy experiments to engender the most efficacious CD8+ responses against epitopes defined in Specific Aim I.